Unraveling Comorbidities Contribution to Cardiac Diastolic Dysfunction and Heart Failure

Area of Science:

• Cardiology
• Pathophysiology
• Translational Medicine

Background:

• Heart failure with preserved ejection fraction (HFpEF) is a significant public health concern.
• HFpEF is associated with multiple comorbidities, complicating the understanding of its underlying pathology.
• Current generalized therapeutic approaches may not address the specific pathological drivers in HFpEF patients.

Purpose of the Study:

• To investigate the distinct contributions of major HFpEF comorbidities to the syndrome's development.
• To elucidate the time-dependent pathological features associated with each comorbidity in HFpEF.
• To identify shared and distinct pathways through which comorbidities drive HFpEF.

Main Methods:

• Utilized distinct mouse models representing key HFpEF comorbidities.
• Conducted a long-term study (2.5 years) to observe disease progression.
• Analyzed cardiac and non-cardiac alterations, including fibrosis, remodeling, and functional impairments.

Main Results:

• Aging, obesity, hypertension, chronic intermittent hypoxia, and hyperglycemia each uniquely contribute to HFpEF development.
• Comorbidities affect HFpEF through partially distinct pathological routes, involving cardiac and non-cardiac alterations.
• Specific findings include delayed ventricular relaxation, fibrosis (kidney, liver, myocardium), pulmonary hypertension, and altered arterial flow.

Conclusions:

• The study provides a comprehensive, time-dependent view of HFpEF progression driven by individual comorbidities.
• Pathological substrates contributing to HFpEF vary significantly depending on the specific comorbidity.
• Identified phenogroups in mouse models align with those observed in human HFpEF patients, supporting translational relevance.